Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN activation is induced by pattern-recognition receptors of the innate immune system that sense pathogen-derived nucleic acids. Cellular responses to type I IFN signaling are orchestrated by a complex network of regulatory pathways that involve both the innate and adaptive immune system. The genetic and molecular dissection of rare Mendelian disorders associated with constitutive overproduction of type I IFN has provided unique insight into cell-intrinsic disease mechanisms that initiate and sustain autoinflammation and autoimmunity and that are caused by disturbances in the intracellular nucleic acid metabolism or in cytosolic nucleic acid–sensing pathways. Collectively, these findings have greatly advanced our understanding of mechanisms that protect the organism against inappropriate immune activation triggered by self nucleic acids while maintaining a prompt and efficient immune response to foreign nucleic acids derived from invading pathogens.


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Literature Cited

  1. Stetson DB, Medzhitov R. 1.  2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24:93–103 [Google Scholar]
  2. Crow YJ, Hayward BE, Parmar R. 2.  et al. 2006. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat. Genet. 38:917–20 [Google Scholar]
  3. Crow YJ, Leitch A, Hayward BE. 3.  et al. 2006. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet. 38:910–16 [Google Scholar]
  4. Wu J, Chen ZJ. 4.  2014. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32:461–88 [Google Scholar]
  5. Lee-Kirsch MA, Wolf C, Kretschmer S. 5.  et al. 2015. Type I interferonopathies—an expanding disease spectrum of immunodysregulation. Semin. Immunopathol. 37:349–57 [Google Scholar]
  6. Sun L, Wu J, Du F. 6.  et al. 2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–91 [Google Scholar]
  7. Wu J, Sun L, Chen X. 7.  et al. 2013. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–30 [Google Scholar]
  8. Ishikawa H, Ma Z, Barber GN. 8.  2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–92 [Google Scholar]
  9. Kato H, Takeuchi O, Sato S. 9.  et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–5 [Google Scholar]
  10. Kawai T, Takahashi K, Sato S. 10.  et al. 2005. IPS-1, an adaptor triggering RIG-I- and MDA5-mediated type I interferon induction. Nat. Immunol. 6:981–88 [Google Scholar]
  11. Hornung V, Ellegast J, Kim S. 11.  et al. 2006. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–97 [Google Scholar]
  12. Goubau D, Schlee M, Deddouche S. 12.  et al. 2014. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates. Nature 514:372–75 [Google Scholar]
  13. Ablasser A, Bauernfeind F, Hartmann G. 13.  et al. 2009. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol. 10:1065–72 [Google Scholar]
  14. Chiu YH, Macmillan JB, Chen ZJ. 14.  2009. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–91 [Google Scholar]
  15. Ivashkiv LB, Donlin LT. 15.  2014. Regulation of type I interferon responses. Nat. Rev. Immunol. 14:36–49 [Google Scholar]
  16. McDermott MF, Aksentijevich I, Galon J. 16.  et al. 1999. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:1133–44 [Google Scholar]
  17. McGonagle D, McDermott MF. 17.  2006. A proposed classification of the immunological diseases. PLOS Med 3e297 [Google Scholar]
  18. Crow YJ. 18.  2011. Type I interferonopathies: a novel set of inborn errors of immunity. Ann. N.Y. Acad. Sci. 1238:91–98 [Google Scholar]
  19. Aicardi J, Goutieres F. 19.  1984. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann. Neurol. 15:49–54 [Google Scholar]
  20. Crow YJ, Manel N. 20.  2015. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15:7429–40 [Google Scholar]
  21. Lebon P, Badoual J, Ponsot G. 21.  et al. 1988. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J. Neurol. Sci. 84:201–8 [Google Scholar]
  22. Ramantani G, Kohlhase J, Hertzberg C. 22.  et al. 2010. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum 62:1469–77 [Google Scholar]
  23. Ramantani G, Hausler M, Niggemann P. 23.  et al. 2011. Aicardi-Goutieres syndrome and systemic lupus erythematosus (SLE) in a 12-year-old boy with SAMHD1 mutations. J. Child Neurol. 26:1425–28 [Google Scholar]
  24. Rice GI, Forte GM, Szynkiewicz M. 24.  et al. 2013. Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2a, RNASEH2b, RNASEH2c, SAMHD1, and ADAR: a case-control study. Lancet Neurol 12:1159–69 [Google Scholar]
  25. Vogt J, Agrawal S, Ibrahim Z. 25.  et al. 2013. Striking intrafamilial phenotypic variability in Aicardi-Goutieres syndrome associated with the recurrent Asian founder mutation in RNASEH2c. Am. J. Med. Genet. A 161A:338–42 [Google Scholar]
  26. Tüngler V, Schmidt F, Hieronimus S. 26.  et al. 2014. Phenotypic variability in a family with Aicardi-Goutières syndrome due to the common A177T RNASEH2b mutation. Case Rep. Clin. Med. 3:153–56 [Google Scholar]
  27. Chowdhury D, Beresford PJ, Zhu P. 27.  et al. 2006. The exonuclease TREX1 is in the SET complex and acts in concert with Nm23-H1 to degrade DNA during granzyme A-mediated cell death. Mol. Cell 23:133–42 [Google Scholar]
  28. Yang YG, Lindahl T, Barnes DE. 28.  2007. TREX1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–86 [Google Scholar]
  29. Wolf C, Rapp A, Berndt N. 29.  et al. 2016. RPA and RAD51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat. Commun. 7:11752 [Google Scholar]
  30. Stetson DB, Ko JS, Heidmann T. 30.  et al. 2008. TREX1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–98 [Google Scholar]
  31. Gall A, Treuting P, Elkon KB. 31.  et al. 2012. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–31 [Google Scholar]
  32. Ablasser A, Hemmerling I, Schmid-Burgk JL. 32.  et al. 2014. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192:5993–97 [Google Scholar]
  33. Gray EE, Treuting PM, Woodward JJ. 33.  et al. 2015. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutieres syndrome. J. Immunol. 195:1939–43 [Google Scholar]
  34. Yan N, Regalado-Magdos AD, Stiggelbout B. 34.  et al. 2010. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11:1005–13 [Google Scholar]
  35. Rice G, Newman WG, Dean J. 35.  et al. 2007. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 80:811–15 [Google Scholar]
  36. Tungler V, Silver RM, Walkenhorst H. 36.  et al. 2012. Inherited or de novo mutation affecting aspartate 18 of TREX1 results in either familial chilblain lupus or Aicardi-Goutieres syndrome. Br. J. Dermatol. 167:212–14 [Google Scholar]
  37. Reijns MA, Rabe B, Rigby RE. 37.  et al. 2012. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149:1008–22 [Google Scholar]
  38. Hiller B, Achleitner M, Glage S. 38.  et al. 2012. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J. Exp. Med. 209:1419–26 [Google Scholar]
  39. Sparks JL, Chon H, Cerritelli SM. 39.  et al. 2012. RNase H2-initiated ribonucleotide excision repair. Mol. Cell 47:980–86 [Google Scholar]
  40. Kind B, Muster B, Staroske W. 40.  et al. 2014. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome. Hum. Mol. Genet. 23:5950–60 [Google Scholar]
  41. Gunther C, Kind B, Reijns MA. 41.  et al. 2015. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J. Clin. Investig. 125:413–24 [Google Scholar]
  42. Mackenzie KJ, Carroll P, Lettice L. 42.  et al. 2016. Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J 35:8831–44 [Google Scholar]
  43. Pokatayev V, Hasin N, Chon H. 43.  et al. 2016. RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med. 213:3329–36 [Google Scholar]
  44. Goldstone DC, Ennis-Adeniran V, Hedden JJ. 44.  et al. 2011. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480:379–82 [Google Scholar]
  45. Rice GI, Bond J, Asipu A. 45.  et al. 2009. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat. Genet. 41:829–32 [Google Scholar]
  46. Lahouassa H, Daddacha W, Hofmann H. 46.  et al. 2012. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13:223–28 [Google Scholar]
  47. Tungler V, Staroske W, Kind B. 47.  et al. 2013. Single-stranded nucleic acids promote SAMHD1 complex formation. J. Mol. Med. 91:759–70 [Google Scholar]
  48. Beloglazova N, Flick R, Tchigvintsev A. 48.  et al. 2013. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. J. Biol. Chem. 288:8101–10 [Google Scholar]
  49. Ryoo J, Choi J, Oh C. 49.  et al. 2014. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat. Med. 20:936–41 [Google Scholar]
  50. Cribier A, Descours B, Valadao AL. 50.  et al. 2013. Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep 3:1036–43 [Google Scholar]
  51. Kretschmer S, Wolf C, Konig N. 51.  et al. 2014. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann. Rheum. Dis. 74:3e17 [Google Scholar]
  52. Clifford R, Louis T, Robbe P. 52.  et al. 2014. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123:1021–31 [Google Scholar]
  53. Rice GI, Kasher PR, Forte GM. 53.  et al. 2012. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat. Genet. 44:1243–48 [Google Scholar]
  54. Liddicoat BJ, Piskol R, Chalk AM. 54.  et al. 2015. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349:62521115–20 [Google Scholar]
  55. Rice GI. Toro DY, Jenkinson EM. 55. , Del et al. 2014. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46:503–9 [Google Scholar]
  56. Richards A, van den Maagdenberg AM, Jen JC. 56.  et al. 2007. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat. Genet. 39:1068–70 [Google Scholar]
  57. Schuh E, Ertl-Wagner B, Lohse P. 57.  et al. 2015. Multiple sclerosis-like lesions and type I interferon signature in a patient with RVCL. Neurol. Neuroimmunol. Neuroinflamm. 2:e55 [Google Scholar]
  58. Lee-Kirsch MA, Gong M, Schulz H. 58.  et al. 2006. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am. J. Hum. Genet. 79:731–37 [Google Scholar]
  59. Gunther C, Hillebrand M, Brunk J. 59.  et al. 2013. Systemic involvement in TREX1-associated familial chilblain lupus. J. Am. Acad. Dermatol. 69:e179–81 [Google Scholar]
  60. Lee-Kirsch MA, Chowdhury D, Harvey S. 60.  et al. 2007. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J. Mol. Med. 85:531–37 [Google Scholar]
  61. Ravenscroft JC, Suri M, Rice GI. 61.  et al. 2011. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am. J. Med. Genet. 155A:235–37 [Google Scholar]
  62. König N, Fiehn C, Wolf C. 62.  et al. 2016. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann. Rheum. Dis. In press. doi: 10.1136/annrheumdis-2016-209841 [Google Scholar]
  63. Rahman A, Isenberg DA. 63.  2008. Systemic lupus erythematosus. N. Engl. J. Med. 358:9929–39 [Google Scholar]
  64. Harley IT, Kaufman KM, Langefeld CD. 64.  et al. 2009. Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat. Rev. Genet. 10:285–90 [Google Scholar]
  65. Blanco P, Palucka AK, Gill M. 65.  et al. 2001. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294:1540–43 [Google Scholar]
  66. Leadbetter EA, Rifkin IR, Hohlbaum AM. 66.  et al. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–7 [Google Scholar]
  67. Lovgren T, Eloranta ML, Bave U. 67.  et al. 2004. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 50:1861–72 [Google Scholar]
  68. Marshak-Rothstein A. 68.  2006. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6:823–35 [Google Scholar]
  69. Baechler EC, Batliwalla FM, Karypis G. 69.  et al. 2003. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. PNAS 100:2610–15 [Google Scholar]
  70. Lee-Kirsch MA, Gong M, Chowdhury D. 70.  et al. 2007. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39:1065–67 [Google Scholar]
  71. Namjou B, Kothari PH, Kelly JA. 71.  et al. 2011. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12:270–79 [Google Scholar]
  72. An J, Briggs TA, Dumax-Vorzet A. 72.  et al. 2016. Tartrate-resistant acid phosphatase deficiency in the predisposition to systemic lupus erythematosus. Arthritis Rheumatol. In press [Google Scholar]
  73. Yasutomo K, Horiuchi T, Kagami S. 73.  et al. 2001. Mutation of DNase1 in people with systemic lupus erythematosus. Nat. Genet. 28:313–14 [Google Scholar]
  74. Al-Mayouf SM, Sunker A, Abdwani R. 74.  et al. 2011. Loss-of-function variant in DNase1L3 causes a familial form of systemic lupus erythematosus. Nat. Genet. 43:1186–88 [Google Scholar]
  75. Manderson AP, Botto M, Walport MJ. 75.  2004. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22:431–56 [Google Scholar]
  76. Liu Y, Jesus AA, Marrero B. 76.  et al. 2014. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371:507–18 [Google Scholar]
  77. Jeremiah N, Neven B, Gentili M. 77.  et al. 2014. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Investig. 124:5516–20 [Google Scholar]
  78. Rutsch F, MacDougall M, Lu C. 78.  et al. 2015. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am. J. Hum. Genet. 96:275–82 [Google Scholar]
  79. Jang MA, Kim EK, Now H. 79.  et al. 2015. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am. J. Hum. Genet. 96:266–74 [Google Scholar]
  80. Briggs TA, Rice GI, Daly S. 80.  et al. 2011. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat. Genet. 43:127–31 [Google Scholar]
  81. Lausch E, Janecke A, Bros M. 81.  et al. 2011. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat. Genet. 43:132–37 [Google Scholar]
  82. Shinohara ML, Lu L, Bu J. 82.  et al. 2006. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat. Immunol. 7:498–506 [Google Scholar]
  83. Bogunovic D, Byun M, Durfee LA. 83.  et al. 2012. Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science 337:1684–88 [Google Scholar]
  84. Zhang X, Bogunovic D, Payelle-Brogard B. 84.  et al. 2015. Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature 517:89–93 [Google Scholar]
  85. Meuwissen MEC, Schot R, Buta S. 85.  et al. 2016. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J. Exp. Med. 213:1163–74 [Google Scholar]
  86. Liu Y, Ramot Y, Torrelo A. 86.  et al. 2012. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 64:895–907 [Google Scholar]
  87. Agarwal AK, Xing C, DeMartino GN. 87.  et al. 2010. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am. J. Hum. Genet. 87:6866–72 [Google Scholar]
  88. Brehm A, Liu Y, Sheikh A. 88.  et al. 2015. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J. Clin. Investig. 125:114196–211 [Google Scholar]
  89. Partington MW, Marriott PJ, Prentice RS. 89.  et al. 1981. Familial cutaneous amyloidosis with systemic manifestations in males. Am. J. Med. Genet. 10:165–75 [Google Scholar]
  90. Starokadomskyy P, Gemelli T, Rios JJ. 90.  et al. 2016. DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat. Immunol. 17:5495–504 [Google Scholar]
  91. Zhou Q, Yang D, Ombrello AK. 91.  et al. 2014. Early-onset stroke and vasculopathy associated with mutations in ADA2. N. Engl. J. Med. 370:911–20 [Google Scholar]
  92. Navon Elkan P, Pierce SB, Segel R. 92.  et al. 2014. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N. Engl. J. Med. 370:10921–31 [Google Scholar]
  93. Uettwiller F, Sarrabay G, Rodero MP. 93.  et al. 2016. ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters. RMD Open 2:1e000236 [Google Scholar]
  94. Bras J, Guerreiro R, Santo GC. 94.  2014. Mutant ADA2 in vasculopathies. N. Engl. J. Med. 371:5478–80 [Google Scholar]
  95. Napirei M, Karsunky H, Zevnik B. 95.  et al. 2000. Features of systemic lupus erythematosus in DNase1-deficient mice. Nat. Genet. 25:177–81 [Google Scholar]
  96. Lood C, Blanco LP, Purmalek MM. 96.  et al. 2016. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22:2146–53 [Google Scholar]
  97. Caielli S, Athale S, Domic B. 97.  et al. 2016. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213:5697–713 [Google Scholar]
  98. Kawane K, Fukuyama H, Kondoh G. 98.  et al. 2001. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292:55211546–49 [Google Scholar]
  99. Ahn J, Gutman D, Saijo S. 99.  et al. 2012. Sting manifests self DNA-dependent inflammatory disease. PNAS 109:4719386–91 [Google Scholar]
  100. Gao D, Li T, Li XD. 100.  et al. 2015. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. PNAS 112:E5699–705 [Google Scholar]
  101. West AP, Khoury-Hanold W, Staron M. 101.  et al. 2015. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:7548553–57 [Google Scholar]
  102. Frémond ML, Rodero MP, Jeremiah N. 102.  et al. 2016. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J. Allergy Clin. Immunol. In press pii:S0091–6749(16)30797-7 doi: 10.1016/j.jaci.2016.07.015 [Google Scholar]

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